lncRNA H19 downregulation mediates oxidative stress-induced osteogenic dysfunction.

Abstract

Age-related bone loss results from an imbalance between bone resorption and formation, which is heavily influenced by senescence of osteoblasts. Oxidative stress and the associated production of reactive oxygen species (ROS) are key contributors to bone aging and impaired bone formation. Our previous study demonstrated that protein arginine deiminase 2 (PADI2) is downregulated by ROS, leading to cellular senescence and impaired osteoblast differentiation. In this study, lncRNA H19 was identified as a critical factor co-regulated by ROS and Padi2 deficiency through mRNA-sequencing analysis. Using a stratified transcriptomic analysis in which genes commonly regulated by ROS and Padi2 deficiency were further classified according to their response to H19 knockdown, we investigated the biological processes associated with H19 in this context. This analysis suggested that H19 is a candidate regulator of osteoblast differentiation under oxidative stress and Padi2 deficiency. H19 knockdown significantly inhibited osteogenic differentiation of MC3T3-E1 cells but did not induce the senescence-associated responses observed following H₂O₂ treatment or Padi2 knockdown. Moreover, H19 overexpression promoted bone repair in a mouse calvarial defect model. Together, these findings provide new insights into the molecular mechanisms underlying bone aging and identify H19 as a potential therapeutic target for promoting osteogenesis.